Bo Li, Ph.D.

Cold Spring Harbor Laboratory

Funded in September, 2009: $200000 for 3 years

Hyperactive brain synapses may be key to depression and its treatment

Investigators will use two-photon molecular imaging in a mouse model of depression to develop direct evidence of cellular changes that cause depression and whether pharmaceutical agents can reverse these changes.

Three types of anti-depressants are marketed for use in people with depression. All three prolong activity of the neurotransmitters serotonin and norepinephrine. Both tricyclic antidepressants and SSRI’s (selective serotonin reuptake inhibitors) prevent neurons sending the transmitters from taking back any excess that is released into the area around the synapse (the junction between two communicating brain cells). The transmitters therefore remain active at the synapse longer. Monomaine oxidase inhibitors act by blocking an enzyme that ordinarily destroys unused transmitter. These three drug types, however, have limited effectiveness; only 30 percent of depressed patients achieve remission, and it takes several weeks before these drugs can ameliorate depressive symptoms. Now recent evidence suggests that synapses that are hyperactive, and transmit glutamate, may be the key target, but their location and molecular changes remain largely unknown,

The investigators’ data indicate that the synapses are located in particular brain regions. They hypothesize that depression-inducing stimuli can cause sustained hyperactivity of these “glutamatergic” synapses in these brain regions, and that suppressing this hyperactivity is critical for effective anti-depressant treatment. Using two-photon imaging and molecular biology techniques, they will compare the brain cells, glutamate receptors, and other aspects of the synapse in a mouse model of depression compared to healthy mice. They then will relate identified biological changes in the mouse depression model to their depressive behaviors. Thereafter, they will determine whether synaptic hyperactivity in general, or specifically related to the neurotransmitter glutamate, is the causal factor. To test this, they will see whether ketamine, an agent that acts on glutamate receptors (but can have major side effects) produces acute and long-lasting effects both on the behavior and synapses in the depressed mouse model. Then they will find out whether an SSRI, which does not target glutamate, also can normalize the hyperactive synapses and affect depressive behaviors in the mice. If so, the findings would suggest that hyperactive synapses are the causal factor in depression.

There is growing evidence that increased NMDA receptor activity and dysfunction of the glutamatergic synapse play an essential role in the pathophysiology of depression. However, the location and the mechanism of the synaptic deficits underlying depression remain largely unknown. Recent studies suggest that particular regions in the prefrontal cortex (PFC) and its interconnected brain regions have increased activity in depressed patients and animal models of depression. Based on these findings and our preliminary results we hypothesize that depression-inducing stimuli can cause sustained glutamatergic synapse hyperactivity in these brain regions, and suppression of this hyperactivity is integral to the efficacy of effective antidepressant treatments. To test this hypothesis, we will examine the PFC and other interconnected brain areas in animal models of depression. We plan to use the two-photon laser scanning microscopy combined with whole-cell patch-clamp recording and molecular biology techniques to identify the cellular, synaptic, and molecular changes, and to determine the relationship between these changes and depressive behaviors.

The specific aims of this proposal are to: 1) identify hyperactive brain regions and neurons in animal models of depression; 2) elucidate the nature of the synaptic hyperactivity in animal models of depression; and 3) determine whether the antidepressant effect of a pharmacological agent can be predicted by its efficacy in normalizing depression-induced synaptic changes. We believe that the proposed research will shed light on the biological mechanisms of depression and guide the identification of direct antidepressant targets.

Bo Li, Ph.D.

Dr. Bo Li is an assistant professor at Cold Spring Harbor Laboratory. He received his Ph.D. in Neuroscience from the University of British Columbia, working with Dr. Lynn Raymond to study the functional regulation of NMDA receptors. He did his postdoctoral research first at Cold Spring Harbor Laboratory then at University of California at San Diego, in the laboratory of Dr. Roberto Malinow, where he worked on glutamate receptor trafficking and synaptic plasticity. Dr. Li’s current interests are to study synaptic mechanisms of normal adaptive behaviors, and disease-related synaptic changes in the brain circuits involved in depression and schizophrenia, using two-photon imaging, electrophysiology, and genetic techniques. His long-term goal is to develop methods that will allow the manipulation of activity in specific brain circuits in order to change disease-related behaviors

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